Discussion
Intestinal macrophages are known as “gatekeepers” for their ability to
clear foreign pathogens by expressing pathogen-associated molecular
patterns (PAMPs) and recognize tissue damage by damage-associated
molecular patterns (DAMPs). They also show tolerance to food or
commensal microbes. Macrophages are a heterogeneous population of innate
immune cells that play diverse functions in immune response and tissue
homeostasis. Although boundaries of the heterogeneous macrophage
population are ambiguous, they can be functionally divided into
pro-inflammatory versus anti-inflammatory macrophages. Macrophage
polarization depends on their microenvironment. Disruption of the
composition or function of macrophages can contribute to various
gastro-intestinal diseases such as IBD. IBD patients show an altered
population of macrophages where inflammatory macrophages are dominant.
These inflammatory macrophages can accumulate in the intestine during
IBD, which can release TNF-α, IL-1β, and IL-6. To overcome IBD,
biologics such as anti-TNF therapy is commonly used since TNF-α is a key
pathological cytokine in IBD. Anti-IL-12/23, anti-integrin,
5-aminosalicylic acids, and immunomodulators can also be used for IBD
therapy. Despite recent advances in IBD therapy, limitations still exist
since complete remission is difficult. Thus, the goal for overcoming IBD
is shifting to targeting mucosal healing.
Since macrophages are deeply involved in regulating inflammation and
mucosal healing, targeting these macrophages can be a good therapeutic
strategy against IBD. Many previous studies targeting macrophages to
induce an anti-inflammatory shift have shown the potential of an
effective IBD therapy. Activation of SIRT1 can promote anti-inflammatory
genes Mrc1 and IL-10 while decreasing pro-inflammatory genes iNOS, CCL2,
IL-12 p35, and IL-12 p40. Anti-inflammatory macrophage polarization by
the SIRT1/adenosine monophosphate-activated protein kinase pathway can
reduce inflammatory responses in a rheumatoid arthritis mouse model (S.
Park et al., 2020; Zhou, Zhang, & Ding, 2022). TLR2/1 agonist PAM3CSK4
can induce monocytes to differentiate into anti-inflammatory macrophages
and reduce DSS-induced colitis in a mouse model (Horuluoglu,
Kayraklioglu, Tross, & Klinman, 2020).
Metabolic pathways in macrophages are deeply involved in the fate of
macrophage polarization. Therefore, reports targeting macrophage
polarization to an anti-inflammatory character by metabolic modulation
is arising as a promising strategy for IBD therapy. Pro-inflammatory
macrophages depend on glycolysis, while anti-inflammatory macrophages
are activated by mitochondrial oxidative phosphorylation (Liu et al.,
2021). Different paths of arginine catabolism contribute to macrophage
polarization. Generation of NO by iNOS favors inflammatory macrophage
polarization, while generation of urea and orthinine by Arg1 favors
anti-inflammatory macrophage polarization. Increased consumption of
L-arginine by iNOS and decreased Arg1 have been shown in ulcerative
colitis. Thus, dietary supplementation of L-arginine can be used as an
IBD therapy (Andrade et al., 2018; Bourgonje et al., 2020).
LMT503 is an NAD+ enhancer by working as an efficient
substrate for NQO1. NQO1 has multiple roles in defending against
cellular stress. NQO1 can detoxify quinones by reducing them into
hydroquinones. At the same time, oxidation of NAD(P)H occurs, which
increases NAD+. Previous studies have shown that
inflammation can be controlled by triggering macrophage shift by
increasing NAD+ level. NAD+synthesis via the kynurenine pathway can shift aged inflammatory
macrophages to an anti-inflammatory state with increased phagocytic
activity (Minhas et al., 2019). Increasing NAD+ by
administration of NAD+ precursor β-nicotinamide
mononucleotide (β-NMN) can shift macrophages to an anti-inflammatory
type during sepsis (Cros et al., 2022). Sirtuins are a family of class
III histone deacetylases known to be dependent on NAD+(Anderson, Madsen, Olsen, & Hirschey, 2017). They consist of seven
members, SIRT1-7. Sirtuins can modulate inflammation via nuclear
factor-kappa B (NF-κB) or activator protein 1 (AP-1). SIRTs except SIRT5
are known to inhibit NF-κB activation by deacetylation of p65 subunit.
SIRT1 cam inhibit IL-1β secretion by down-regulating NLRP3 inflammasome
(S. Park et al., 2020). SIRT1, SIRT3, and SIRT6 can decrease AP-1
transcriptional activity which controls pro-inflammatory cytokine
production (Palomer et al., 2020; Zhang et al., 2010). Treatment of
BMDMs with LMT503 increased SIRT1, 3, and 6.
In summary, this study found that NAD+ enhancement
alleviated intestinal inflammation by reinforcing immune regulatory
character of tissue resident CX3CR1+macrophages. NAD+ enhancement was achieved by LMT503,
an efficient substrate for NQO1. Metabolic reprograming in macrophages
treated with LMT503 down-regulated inflammatory markers TNF-α and iNOS
but up-regulated anti-inflammatory IL-10 and Arg1 during colitis.
NAD+ enhancement of colonic
CX3CR1+ macrophages was crucial for
ameliorating DSS-induced colitis in mice since LMT503 treatment did not
show any effect when CX3CR1+macrophages were depleted. Our study suggests that LMT503 is a potential
IBD therapy candidate that can drive anti-inflammatory macrophage
polarization via immuno-metabolic modulation.